The NLRP3/eIF2 axis in acute myeloid leukemia

Activity: Talk or presentationOral presentationscience to science / art to art

Description

The NLR family pyrin domain containing 3 (NLRP3) inflammasome has lately attracted great attention in various biomedical fields, as excessive activation of the NLRP3 inflammasome plays an important role in many different pathologies including hematologic diseases. In this context, our study highlights a novel function of the NLRP3 inflammasome in Acute Myeloid Leukemia (AML). We demonstrate that NLRP3 inflammasome components and the inflammasome-related cytokines IL-18 and IL-1b are overexpressed in AML patients, resulting in poor survival rates. Using shotgun proteomics, we could identify the eIF2 pathway as an important novel NLRP3 target. Genetic knockdown or pharmacological inhibition of NLRP3 results in enhanced eIF2a phosphorylation, which in turn was linked to the inhibition of cell cycle progression and apoptosis in vitro and in vivo. Additionally, a strong decrease in the cyclin-dependent kinases CDK4 and CDK6 was observed, also accompanied by an upregulation of the CDK inhibitor p21 (CDKN1A), resulting in pronounced cell cycle arrest in the G0/G1 phase and increased apoptosis. Taken together, these findings suggest that NLRP3 overexpression, as observed in many AML patients, blocks apoptosis of leukemic cells by dysregulating the eIF2 signaling pathway. Our data suggest that the NLRP3/eIF2 axis acts as a novel driver of cell cycle progression in AML. As AML is a disease with extremely low survival rates and limited treatment options, a better understanding of the molecular mechanism linking inflammation to excessive cell proliferation may open new paths for novel treatment strategies.
Period14 Sept 202316 Sept 2023
Event titleÖGAI Annual Meeting 2023
: 51th Annual Meeting of the Austrian Society for Allergology and Immunology
Event typeConference
LocationLinz, AustriaShow on map
Degree of RecognitionNational

Fields of Science and Technology Classification 2012

  • 301 Medical-Theoretical Sciences, Pharmacy